What is the mechanism of action of this treatment?

Immune checkpoint inhibitors, such as PD-1 inhibitors (e.g., Zimberelimab) and TIGIT inhibitors (e.g., Domvanalimab), work by blocking proteins that prevent the immune system from attacking cancer cells. PD-1 inhibitors block the PD-1 protein on T-cells, enhancing the immune response against cancer cells. TIGIT inhibitors block the TIGIT protein, which also helps to activate T-cells and enhance the immune response. These mechanisms are crucial for NSCLC patients because they help the body's immune system recognize and destroy cancer cells, potentially leading to better outcomes and prolonged survival.

What side effects are associated with this type of intervention?

Common treatments for Non-Small Cell Lung Cancer (NSCLC) involving immune checkpoint inhibitors such as PD-1 inhibitors (e.g., pembrolizumab, nivolumab) and chemotherapy are associated with several side effects. PD-1 inhibitors can cause immune-related adverse events, including pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions. Chemotherapy often leads to side effects such as neutropenia, febrile neutropenia, anemia, fatigue, nausea, vomiting, and increased risk of infections. Combining these therapies can enhance efficacy but also increases the likelihood of experiencing these adverse effects.

What prior FDA approvals exist?

Several immune checkpoint inhibitors have received FDA approval for the treatment of Non-Small Cell Lung Cancer (NSCLC). Pembrolizumab, a PD-1 inhibitor, is approved for use in combination with chemotherapy for both squamous and non-squamous NSCLC, as well as a monotherapy for tumors expressing PD-L1. Nivolumab, another PD-1 inhibitor, is approved for previously treated advanced NSCLC. Atezolizumab, a PD-L1 inhibitor, is approved in combination with chemotherapy for first-line treatment of metastatic NSCLC. These approvals highlight the effectiveness of immune checkpoint inhibitors in NSCLC treatment, similar to the investigational drugs Zimberelimab and Domvanalimab being studied in combination with chemotherapy.

What other types of research exist?

Promising novel alternatives for NSCLC patients include: 1) Atezolizumab (PD-L1 inhibitor) combined with Bevacizumab (anti-VEGF) based on its success in the IMbrave150 trial for HCC, which may translate to NSCLC. 2) Durvalumab (PD-L1 inhibitor) combined with Tremelimumab (CTLA-4 inhibitor), which has shown improved overall survival in the HIMALAYA trial for HCC. 3) Penpulimab (PD-1 inhibitor) combined with Anlotinib (multi-targeted tyrosine kinase inhibitor), which is being evaluated for its efficacy and safety in other cancers and may be applicable to NSCLC.

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Chemotherapy

Immunotherapy + Chemotherapy for Non-Small Cell Lung Cancer (STAR-121 Trial)

Phase 3

Waitlist Available

Research Sponsored by Gilead Sciences

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Pathologically documented NSCLC with documented evidence of Stage IV disease at the time of enrollment

Not received prior systemic treatment for metastatic NSCLC

Must not have

Allogenic tissue/solid organ transplant

Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 58 months

Awards & highlights

No Placebo-Only Group

Pivotal Trial

Summary

This trial is testing two new drugs, zimberelimab and domvanalimab, combined with chemotherapy for patients with advanced lung cancer that has spread and lacks specific genetic targets. These drugs help the immune system better recognize and attack cancer cells. The goal is to see if this combination improves survival compared to another drug, pembrolizumab, with chemotherapy.

Who is the study for?

This trial is for adults with untreated metastatic non-small cell lung cancer without certain genetic mutations. Participants should have a good performance status, no prior treatments targeting immune checkpoints, and no history of severe lung conditions or active autoimmune diseases. Pregnant or breastfeeding individuals are excluded.

What is being tested?

The study compares the effectiveness of two immunotherapy drugs (Zimberelimab and Domvanalimab) combined with chemotherapy against Pembrolizumab with chemotherapy in extending life and delaying cancer progression in patients.

What are the potential side effects?

Possible side effects include reactions related to the immune system attacking normal organs, infusion-related reactions, fatigue, nausea, blood count changes, increased risk of infections and potential allergic responses to drug components.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My lung cancer is at stage IV.

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I haven't had systemic treatment for advanced lung cancer.

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I am fully active or can carry out light work.

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My tests for EGFR and ALK mutations are negative.

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My cancer does not have genetic changes treatable by specific drugs.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have received a transplant from another person.

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I have an active hepatitis B or C infection.

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I have not received a live-virus vaccine in the last 30 days.

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I have or had lung inflammation that needed steroids.

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I have significant fluid buildup in my body.

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My lung cancer is a mix of small cell and non-small cell types.

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I have been treated with drugs targeting the immune system.

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I have brain metastases or carcinomatous meningitis that haven't been treated.

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I am on long-term steroid medication.

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I have been treated for an autoimmune disease in the last 2 years.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 58 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 58 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 58 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Overall Survival (OS)

Progression-free Survival (PFS) as Assessed by Blinded Independent Central Review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

Secondary study objectives

Duration of Response (DOR) as Assessed by BICR per RECIST Version 1.1

Objective Response Rate (ORR) as Assessed by BICR per RECIST Version 1.1

Time to First Symptom Deterioration in Non-small Cell Lung Cancer Symptom Assessment Questionnaire (NSCLC-SAQ) Total Score

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Pivotal Trial

The final step before approval, pivotal trials feature drugs that have already shown basic safety & efficacy.

Trial Design

3Treatment groups

Experimental Treatment

Active Control

Group I: Zimberelimab (ZIM) +Domvanalimab (DOM) + ChemotherapyExperimental Treatment7 Interventions

Participants will receive ZIM 360 mg + DOM 1200 mg (up to 35 doses) with chemotherapy every 3 weeks (Q3W) on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin area under the concentration versus time curve (AUC)5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles. After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Group II: Zimberelimab (ZIM) + ChemotherapyExperimental Treatment6 Interventions

Participants will receive ZIM 360 mg (up to 35 doses) with chemotherapy Q3W on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin AUC 5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Group III: Pembrolizumab (PEMBRO) + ChemotherapyActive Control6 Interventions

Participants will receive PEMBRO 200 mg (up to 35 doses) with chemotherapy Q3W on Day 1 of each 21-day cycle. Choice of chemotherapy is dependent on histology. * Participants with nonsquamous histology will receive cisplatin 75 mg/m\^2 or carboplatin AUC 5 + pemetrexed 500 mg/m\^2 Q3W for first 4 cycles. After the completion of the first 4 cycles, participants with nonsquamous histology may continue with maintenance pemetrexed 500 mg/m\^2 Q3W until disease progression or intolerable toxicities. * Participants with squamous histology will receive carboplatin AUC 6 Q3W with paclitaxel 200 mg/m\^2 Q3W or nab-paclitaxel 100 mg/m\^2 weekly (QW) for first 4 cycles.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Zimberelimab

2020

Completed Phase 2

~230

Carboplatin

2014

Completed Phase 3

~6120

Cisplatin

2013

Completed Phase 3

~3120

Paclitaxel

2011

Completed Phase 4

~5370

Nab-paclitaxel

2014

Completed Phase 3

~1950

Pemetrexed

2014

Completed Phase 3

~5550

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Immune checkpoint inhibitors, such as PD-1 inhibitors (e.g., Zimberelimab) and TIGIT inhibitors (e.g., Domvanalimab), work by blocking proteins that prevent the immune system from attacking cancer cells. PD-1 inhibitors block the PD-1 protein on T-cells, enhancing the immune response against cancer cells. TIGIT inhibitors block the TIGIT protein, which also helps to activate T-cells and enhance the immune response. These mechanisms are crucial for NSCLC patients because they help the body's immune system recognize and destroy cancer cells, potentially leading to better outcomes and prolonged survival.

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11).